MEN2A and MEN2B should be suspected in any patient diagnosed with MTC or pheochromocytoma, particularly when the age of presentation is very young (younger than 35). MTC most commonly presents with a solitary thyroid nodule and/or cervical lymphadenopathy. Any patient with diagnosed MTC or family history of MTC should be tested for RET proto-oncogene mutations for both MEN2A and MEN2B. The patients who are diagnosed with pheochromocytoma at the age earlier than that of its sporadic forms should be tested for MEN2A and MEN2B. The classic symptoms of pheochromocytoma are the paroxysms of a headache, anxiety, diaphoresis and palpitations, and high blood pressure. The presence of these symptoms in the third decade, particularly in between 25 and 32 years, should prompt to screen for MEN2.

A detailed history of the presence of associated conditions (described above) in the patient or the family members should be taken. Other possible physical examination findings include marfanoid habitus (decreased upper to lower body ratio), mucosal neuromas (red papules) over lips and tongues, and joint hyperlaxity associated with MEN2B. The patients typically lack lens dislocation or aortic abnormalities, unlike Marfan syndrome. MEN2A also is suspected in patients with clinical features like purity, scaly, pigmented papules in the interscapular region as these are features of CLA that have an association with MEN2A.

Patients with classic clinical manifestations of MEN2 are evaluated for two main reasons:

1. To screen for other associated common tumors to decrease overall morbidity and mortality
2. To screen for genetic mutation so that other family members should be tested and provided adequate prophylactic medical and surgical care such as prophylactic thyroidectomy

As the most common presentation of both MEN2A and MEN2B is MTC, any patient presenting with a cold, solitary nodule and cervical lymphadenopathy must be evaluated further for the possibility of MTC. The clinical presentation of sporadic MTC is the same as genetic MTC except the latter appears early in life. For this reason, the patient should be biopsied by fine-needle aspiration (FNA) to identify MTC and genotyping should be done for underlying potential RET mutations in the patient as well as first-degree family members.

In an asymptomatic patient identified with high serum calcitonin level or genetic testing (tested for positive family history), MTC is often identified in a preneoplastic state such as neoplastic C-cell hyperplasia. The presence of C-cell hyperplasia is defined based upon microscopy criteria: an increased number of diffusely scattered C-cells (greater than or equal to 7 per thyroid follicle), distribution of C-cells beyond the normal anatomical location, or the follicles completely surrounded by C-cells. Neoplastic C-cell hyperplasia is differentiated from reactive or secondary C-cell hyperplasia as the nests of C cells appear to extend beyond the basement membrane to infiltrate and destroy thyroid follicles.

It is less likely for pheochromocytoma to precede MTC in MEN2. Any patient with the diagnosed pheochromocytoma must be evaluated further for associated tumors by appropriate biochemical and radiological screening and RET genotyping.

The presence of primary hyperthyroidism alone does not indicate for further testing as their is less than 20% association with MEN2A and no association with MEN2B.

Genetic Testing

The genetic testing for RET proto-oncogene is employed to diagnose and identify a specific type of mutation present in an index patient ( the first affected member of the family) such as high-risk, moderate-risk or low-risk mutations. The type of mutations not only determine the expressivity and penetrance of the disease but also spares the effort to test for all the possible mutations in all the family members and determine when to start the screening process for associated tumors and when to do the prophylactic surgery.[8]

For an index patient with suspected MEN2A, evaluation begins with testing for the most common mutated codons in exons 10 and 11, and if negative, we move on to look for other common mutations in descending order. The risk of MTC is low if no germline mutation is found. In this case, sequencing the entire RET coding region to identify a RET mutation is an option.

The same is done for the index patient with MEN2B phenotype. The patient is initially tested for common mutations like a mutation in RET codon M918T in exon 16, and if negative, for the A883F mutation in exon 15. These two mutations are responsible for more than 95% of cases of MEN 2B. If no mutations are identified, the entire RET coding region should be sequenced.

Although, it is rare that patients with classic MEN2A and MEN2B phenotype have no identifiable RET mutation, the presence of at least two of the classical features of MEN2A (MTC, pheochromocytoma, primary hyperparathyroidism) or the presence of  majority of clinical features of MEN2B (MTC, pheochromocytoma, mucosal neuromas, Marfanoid habitus, intestinal ganglioneuromas, myelinated corneal nerves) are enough to make a clinical diagnosis.

Other cases in which genetic testing can be considered: 

• First-degree relatives of a patient with proven germline RET mutation
• Parents whose infants or young children have the clinical characteristics of MEN 2B
• Patients with CLA
• Families whose infants or young children have Hirschsprung disease

Only a small blood sample is required for RET genotyping; therefore, it can be performed at or soon after birth. At the latest, genotyping should be done before time so that prophylactic thyroidectomy could be performed in the event of a positive result.[3]

Biochemical and Radiological Testing

Once the RET genotyping is positive in index patients or an asymptomatic patient with positive family history, biochemical and radiological screening for other tumors is started as described below.

Medullary Thyroid Cancer

Children with certain RET mutations can develop clinically apparent MTC at an early age. The goal for screening in patients with known RET mutations but without clinically apparent disease is to perform a prophylactic thyroidectomy before MTC develops or when it is still confined to the thyroid gland.

For children tested positive for high-risk mutations, monitoring starts at three years of age, and for children with moderate risk mutations, monitoring starts at five years of age. Testing includes the following:

• An annual physical examination
• Neck ultrasound
• Serum calcitonin concentration

Serum calcitonin concentration correlates with the size of the tumor but those with small tumors or neoplastic C-cell hyperplasia, serum calcitonin levels may be normal, and specific stimulation tests like calcium or pentagastrin infusion can be used to confirm the diagnosis. The detection of a serum calcitonin level (basal or stimulated) above the upper limit of normal is an indication for surgery.[8]

Pheochromocytoma

The risk of developing pheochromocytoma is also variable depending upon genotype. Due to screening programs, pheochromocytomas may be diagnosed at a young age and before symptoms are present.

For children in the high-risk categories, annual screening for pheochromocytoma should begin by age 11 years. For children in the moderate-risk category, annual screening starts at 16 years of age. Screening tests include plasma fractionated metanephrines or 24-hour urinary metanephrines and normetanephrine. If biochemical results are positive, the next step is adrenal imaging with CT or MRI. If initial imaging is unable to identify the unilateral versus bilateral disease, adrenal venous sampling can be done.

Hyperparathyroidism

Hyperparathyroidism (only associated with MEN2A) is often mild and asymptomatic. The mean age at diagnosis was 33 years according to one study. Annual biochemical screening starts at the age of 11 years for high-risk patients and by the age of 16 for moderate risk patients. The test of choice for screening is serum calcium corrected for albumin levels. If elevated, serum parathyroid hormone (PTH) is measured, and the diagnosis is established with high or inappropriately high levels of serum PTH in the presence of hypercalcemia.

Medullary Thyroid Carcinoma (MTC)

Virtually, all patients with MEN2A and MEN2B develop MTC. The disease is usually bilateral and multicentric including its precursor neoplastic C-cell hyperplasia. The disease in MEN2B may be more aggressive than MEN2A. The aggressiveness of the disease in each syndrome depends upon the type of mutation.

For the patients with a predisposition to MEN2B, total prophylactic thyroidectomy with lymph node dissection is indicated at 1 year of age as the metastatic disease have been reported in such patients soon after age 1. The lymph nodes are removed even when there is no evidence of involvement.[7]

For the patients with high-risk mutations of MEN2A, total thyroidectomy with lymph node dissection is indicated at age 5. 

For the patients with moderate-risk mutations, the surgery can wait until late childhood or early adulthood. The treatment aims to remove the thyroid gland before it becomes inoperable. Total thyroidectomy is the only way considering bilateral and multicentric nature of the hereditary forms of MTC. Before doing the surgery, it is compulsory to rule out the presence of pheochromocytoma, and if present, it should be removed first.[9]

Pheochromocytoma

Nearly 40% of the patients with MEN2A and 50% with MEN2B develop pheochromocytoma which is also likely to be bilateral and multicentric than its sporadic forms. Bilateral adrenalectomy is recommended in patients who have bilateral pheochromocytoma or if there is unilateral disease, but there is a history of an aggressive bilateral tumor in one of the family members.

The patients with unilateral pheochromocytoma and normal-appearing contralateral glands, unilateral adrenalectomy is recommended because in patients who have undergone unilateral adrenalectomy and developed a contralateral tumor, later on, the chances of metastatic pheochromocytoma were found minimal and no death has even been reported due to catecholamine crisis in patients with MEN2. [10]

Prior to unilateral or bilateral adrenalectomy, patients should be treated with alpha-blockade preoperatively; the patient should receive glucocorticoid stress coverage while awaiting transfer to the surgery.

Primary Hyperparathyroidism

Primary hyperparathyroidism has only 10% to 25% association with MEN2A, and it does not occur at all in MEN2B families. Prophylactic parathyroidectomy is not recommended in asymptomatic patients as the disease is usually mild, appears late, and is often clinically obscure. Surgery is reserved for the patients who develop worsening hypercalcemia, bone loss, and renal impairment. So, instead of removing the gland, the patient is monitored with serum calcium, creatinine, and bone density every 1 or 2 years. The disease is usually multiglandular, and parathyroidectomy is done only when the disease becomes clinically apparent and progressive. Again, the patient should be screened for concurrent pheochromocytoma, and if present, adrenalectomy is done before parathyroidectomy.

• Familial hyperparathyroidism

• Familial hypocalciuric hypercalcemia

• Multiple endocrine neoplasia type 1

• Sturge-Weber syndrome

• Tuberous sclerosis

• Von Hippel-Lindau syndrome

• Von Recklinghausen disease

MEN2 is a group of rare familial cancer syndrome with high penetrance and variable expressivity. Most common organs affected by this condition are endocrine glands like thyroid glands, adrenal glands and parathyroid glands among other tissues which are derived from neural crest cells. As 25% of the patients diagnosed with Medullary thyroid cancer (MTC) have underlying RET proto-oncogene mutations, it is pertinent to screen for genetic mutations and other associated common tumors with the help of biochemical and radiological screening. First degree relatives also should be counseled for genetic testing so that they can also be provided with adequate prophylactic medical and surgical care to decrease overall morbidity and mortality. For MTC, the whole thyroid gland should be excised even if it is in the pre-neoplastic stage, but It is extremely necessary to perform adrenalectomy before thyroidectomy to avoid fatal complications during the surgery. Prior to unilateral or bilateral adrenalectomy, patients should be treated with alpha-blockade preoperatively and also should receive glucocorticoid stress coverage while awaiting transfer to the surgery.[11][12] Due to the challenges in diagnosis, treatment, and follow up a team approach involving specialty nurses, clinicians, and a pharmacist will produce the best result. [Level V]